Ophthalmic compositions containing a synergistic combination of three polymers

ABSTRACT

Ophthalmic compositions suitable for use as artificial tears or as vehicles for ophthalmic drugs are disclosed. The compositions contain a combination of three polymers that have a synergistic effect on viscosity.

[0001] This application claims priority to U.S. Provisional Application,Ser. No. 60/478,713 filed Jun. 13, 2003.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to pharmaceutical compositions. Inparticular, this invention relates to topically administrable ophthalmiccompositions that contain three polymeric components.

[0004] 2. Description of Related Art

[0005] The use of polymeric ingredients in topically administrableophthalmic compositions is well known. Polymeric ingredients aretypically used in suspension compositions as physical stability aids,helping to keep the insoluble ingredients suspended or easilyredispersible. In solution compositions, polymeric ingredients aretypically used to increase the composition's viscosity.

[0006] Many polymers have been used in topically administrableophthalmic compositions. Included among these are cellulosic polymers,such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, andethylhydroxyethyl cellulose. Also included are synthetic polymers, suchas carboxyvinyl polymers and polyvinyl alcohol. Still others includepolysaccharides such as xanthan gum, guar gum, and dextran.

[0007] Combinations of polymers have also been used in ophthalmiccompositions. Certain combinations of polymers are known to providesynergistic effects on viscosity and, in some cases, even a phasetransition from a liquid to a gel. For example, U.S. Pat. No. 4,136,173discloses ophthalmic compositions containing a combination of xanthangum and locust bean gum.

[0008] One approach to achieving a target viscosity in a topicallyadministrable ophthalmic composition might involve simply adding asufficient amount of one polymeric ingredient. Often, however, it isdesirable to minimize the total amount of polymeric additives intopically administrable ophthalmic compositions. A mixed polymer systemcontaining more than one polymer can significantly enhance the viscosityand lubrication property of a composition while minimizing total polymerconcentration and cost of materials.

SUMMARY OF THE INVENTION

[0009] The present invention is directed toward ophthalmic compositionsthat contain three polymeric components. The compositions containhydroxypropyl methylcellulose and a combination of two polymers selectedfrom the group of combinations consisting of guar gum and a carboxyvinylpolymer; guar gum and hydroxyethyl cellulose; guar gum and dextran;hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and acarboxyvinyl polymer. The compositions are useful as artificial tearproducts, but can also serve as vehicles for delivering ophthalmicdrugs.

[0010] The present invention is based upon the finding that thespecified combinations of three polymers have a synergistic effect onviscosity.

BRIEF DESCRIPTION OF THE DRAWING

[0011]FIG. 1 shows the viscosity for each of Compositions 1-8 (Example2), demonstrating the remarkable synergy among the three polymer system:hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer.

[0012]FIG. 2 shows the effect of total polymer concentration onviscosity for the three polymer system of hydroxypropyl methylcellulose,guar gum and carboxyvinyl polymer for a concentration ratio of 3:1:1(hydroxypropyl methylcellulose:guar gum:carboxyvinyl polymer) at pH 7.0.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Unless otherwise indicated, all ingredient concentrations arelisted as a weight/volume percentage basis (% w/v).

[0014] The ophthalmic compositions of the present invention are aqueouscompositions that include a combination of three polymeric ingredients:hydroxypropyl methylcellulose (“HPMC”) and a combination of two polymersselected from the group of combinations consisting of guar gum (“Guar”)and a carboxyvinyl polymer (“carbomer”); Guar and hydroxyethyl cellulose(“HEC”); Guar and dextran; HEC and carbomer; and dextran and carbomer.All of these types of polymers are known and have been used inophthalmic compositions. All of these types of polymers are alsocommercially available.

[0015] HPMC is commercially available from the Dow Chemical Companyunder the brand name Methocel®. HPMC is available in a variety ofgrades. Most preferred for use in the compositions of the presentinvention is Methocel E4M, (HPMC 2910), which has a number averagemolecular weight of approximately 86,000 dalton. The concentration ofHPMC in the compositions of the present invention will generally rangefrom 0.05-0.5%, and will preferably be 0.3%.

[0016] Guar includes guar gum and guar gum derivatives, such as thehydroxypropyl or hydroxypropyltrimonium chloride derivatives of guargum. Guar and its derivatives are described in U.S. Pat. No. 6,316,506,the entire contents of which are hereby incorporated by reference. Forpurposes of the present application, guar includes unsubstituted guargum and its substituted derivatives. Guar gum and many of itsderivatives are commercially available from Rhone-Poulenc (Cranbury,N.J.), Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp,Md.). A preferred derivative for use in the compositions of the presentinvention is hydroxypropyl guar (“HP-Guar”). The concentration of guarin the compositions of the present invention will generally range from0.01-0.2%, and will preferably be 0.1%.

[0017] Carboxyvinyl polymers suitable for use in the present inventionare also known as “carbomers” or carboxypolymethylene. They arecommercially available from sources such as Noveon, Inc. (Cleveland,Ohio), which distributes them under the trade name Carbopol®. Carbopolpolymers are crosslinked, acrylic acid-based polymers. They arecross-linked with allyl sucrose or allylpentaerythritol. Carbopolcopolymers are polymers of acrylic acid, modified by C₁₀₋₃₀ alkylacrylates, and crosslinked with allylpentaerythritol. A preferredcarbomer for use in the compositions of the present invention is apolymer of acrylic acid cross-linked with allyl sucrose orallylpentaerythritol, which is commercially available as Carbopol® 974P.The concentration of carbomer in the compositions of the presentinvention will generally range from 0.01-0.2%, and will preferably be0.1%.

[0018] HEC is commercially available from Hercules Inc. (AqualonDivision) in a variety of grades, including Natrasol 250 LR, Natrasol250 MR and Natrasol 250 HR. A preferred HEC for use in the compositionsof the present invention is the NF grade material, which is commerciallyavailable as Natrasol 250HR. The concentration of HEC in thecompositions of the present invention will generally range from0.05-0.5%, and will preferably range from 0.1-0.2%.

[0019] Dextran is commercially available from Amresco in a variety ofgrades, including Dextran 5, 10, 20, 40, 70, 110, 500, and 2000. Apreferred dextran for use in the compositions of the present inventionis Dextran 70 (NOC grade; dry powder). The concentration of dextran inthe compositions of the present invention will generally range from0.01-0.2%, and will preferably be 0.1%.

[0020] The aqueous compositions of the present invention contain thethree specified polymeric ingredients in a ratio ranging from 1:1:1 to3:3:3, with a ratio of 3:1:1 being most preferred, where the amount ofHPMC is listed first and the amounts of the other two polymers arelisted second and third, respectively. The total concentration of thethree polymeric ingredients should range from 0.1-1%, preferably0.3-0.9%, and most preferably, 0.4-0.7%.

[0021] In addition to the three required polymeric ingredients, theaqueous compositions of the present invention may contain otheringredients as excipients. For example, the compositions may include oneor more pharmaceutically acceptable buffering agents, preservatives(including preservative adjuncts), non-ionic tonicity-adjusting agents,surfactants, solubilizing agents, stabilizing agents, comfort-enhancingagents, emollients, pH-adjusting agents and/or lubricants. Preferably,the aqueous composition does not contain any polymeric ingredients,other than the synergistic combination of the three polymericingredients specified above, with the exception of polymericpreservatives for compositions that contain a preservative. If thecompositions contain a carbomer as one of the three polymers, then thecompositions of the present invention do not contain any ionictonicity-adjusting agents, such as sodium chloride, or other ionicexcipients, such as boric acid, as these ingredients have a significant,detrimental effect on the composition's viscosity.

[0022] The compositions of the invention have a pH in the range of 5-9,preferably 6.5-7.5, and most preferably 6.9-7.4. If the compositionscontain a carbomer as one of the three polymers, it is critical that thecompositions are formulated so that the target pH is not exceeded. Oncea target pH has been exceeded in compositions containing a carbomer,adding an acid such as hydrochloric acid to adjust the pH downward cancompromise the synergistic viscosity. Even relatively small amounts ofacid or salts, on the order of 0.005%, can have a significant effect onthe viscosity of compositions containing a carbomer.

[0023] The compositions of the present invention generally have anosmolality in the range of 220-320 mOsm/kg, and preferably have anosmolality in the range of 235-260 mOsm/kg.

[0024] The aqueous compositions of the present invention are suitablefor use as artificial tear products to relieve symptoms of dry eye.Alternatively, the compositions of the present invention may act as avehicle for an ophthalmic drug. Ophthalmic drugs suitable for use in thecompositions of the present invention include, but are not limited to:anti-glaucoma agents, such as beta-blockers including timolol,betaxolol, levobetaxolol, carteolol, miotics including pilocarpine,carbonic anhydrase inhibitors, prostaglandins, seretonergics,muscarinics, dopaminergic agonists, adrenergic agonists includingapraclonidine and brimonidine; anti-angiogenesis agents; anti-infectiveagents including quinolones such as ciprofloxacin, and aminoglycosidessuch as tobramycin and gentamicin; non-steroidal and steroidalanti-inflammatory agents, such as suprofen, diclofenac, ketorolac,rimexolone and tetrahydrocortisol; growth factors, such as EGF;immunosuppressant agents; and anti-allergic agents includingolopatadine. The ophthalmic drug may be present in the form of apharmaceutically acceptable salt, such as timolol maleate, brimonidinetartrate or sodium diclofenac. Compositions of the present invention mayalso include combinations of ophthalmic drugs, such as combinations of(i) a beta-blocker selected from the group consisting of betaxolol andtimolol, and (ii) a prostaglandin selected from the group consisting oflatanoprost; 15-keto latanoprost; travoprost; and unoprostone isopropyl.In the case of a cationic drug, the amount of drug and/or the amount ofcarboxyvinyl polymer and/or the identity and amount of other formulationingredients may need to be adjusted to minimize or eliminateinteractions between the carboxyvinyl polymer and the cationic drug.Preferably, the ophthalmic drug is a neutral or negatively-charged drug.

[0025] Although the amount of drug included in the compositions of thepresent invention will be whatever amount is therapeutically effectiveand will depend upon a number of factors, including the identity andpotency of the chosen drug, the total concentration of drug willgenerally be about 5% or less.

[0026] The compositions of the present invention are preferably notformulated as solutions that undergo a phase transition to a gel uponadministration to the eye. The compositions illustrated in the Examplesbelow do not gel upon administration to the eye.

[0027] The following examples are presented to illustrate furthervarious aspects of the present invention, but are not intended to limitthe scope of the invention in any respect.

EXAMPLES Example 1 Artificial Tear Composition

[0028] A representative formulation for an artificial tear productaccording to the present invention is shown in Table 1. TABLE 1Ingredients Concentration (% w/w) HPMC 2910 0.3 HP-Guar 0.1 Carbopol974P 0.1 Mannitol 4.0 NaOH/HCl qs to pH 7.0 Purified water qs to 100

[0029] The composition shown in Table 1 can be prepared by at least twomethods. One method involves adding the following ingredients slowly andin the following order to heated purified water (70-80° C.)(approximately 80% of the desired batch volume) with mixing: mannitol,HPMC 2910, Carbopol 974P, and HP-Guar (waiting until each ingredient ismixed well before adding the next). pH is then adjusted with 1N NaOH,and the remaining amount of purified water is added. The composition isthen autoclaved at 121° C. for thirty minutes and subsequently cooled toroom temperature with constant stirring.

[0030] An alternative method of preparing the composition shown in Table1 is as follows. In a first container, add heated purified water (70-80°C.) (approximately 60% of the desired batch volume), then mix inmannitol, then HPMC 2910, and then Carbopol 974P, waiting until eachingredient is mixed well before adding the next. Autoclave the resultingcomposition at 121° C. for thirty minutes, then allow the composition tocool to room temperature with constant stirring (“the HPMC/Carbopolcomposition”). In a separate container, add purified water(approximately 30% of the desired batch volume), then mix in HP-Guar.Adjust the pH of the HP-Guar composition with 1N NaOH to pH 9. Autoclavethe HP-Guar composition at 121° C. for thirty minutes, then allow it tocool to room temperature with constant stirring (“the HP-Guarcomposition”), then aseptically combine the HP-Guar composition with theHPMC/Carbopol composition, and aseptically adjust the final pH to 7.0,if necessary, with 1N NaOH and/or 1N HCl.

Example 2 Synergistic Effect on Viscosity (HPMC+Guar+Carbomer)

[0031] The compositions shown in Table 2 were prepared and theirviscosity determined using a Brookfield cone/plate viscometer withnumber 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples(viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25°C.) for more viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 2 and in FIG. 1. TABLE 2 Composition (% w/v)Ingredient 1 2 3 4 5 6 7 8 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC— 0.3 — — 0.3 0.3 — 0.3 2910 Carbopol — — 0.1 — 0.1 — 0.1 0.1 974PHP-Guar — — — 0.1 — 0.1 0.1 0.1 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. pH pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0Purified q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Water 100 100 100 100100 100 100 100 Viscosity 1.1 8.2 488.1 5.3 1339.5 32.3 1273.0 2477.0(cps) Subst. — — — — — — — Yes Synergy^(@)

Example 3 Synergistic Effect on Viscosity (HPMC+HEC+Guar;HPMC+HEC+Carbomer)

[0032] The compositions shown in Table 3 were prepared and theirviscosity determined using a Brookfield cone/plate viscometer withnumber 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples(viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25°C.) for more viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 3. TABLE 3 Composition (% w/v) Ingredient 910 11 12 13 14 15 16 17 18 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.04.0 HPMC — 0.3 — — — 0.3 — — 0.3 0.3 2910 HP-Guar — — 0.1 — — — 0.1 —0.1 — Carbopol — — — 0.1 — — — 0.1 — 0.1 974P Natrasol — — — — 0.1 0.10.1 0.1 0.1 0.1 250HR NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. q.s. pH pH pH pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.07.0 7.0 Purified q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Water100    100    100    100    100    100    100    100    100    100   Viscosity 1.0 8.0 5.2 465.9  3.0 27.7  10.9  642.0  62.8  1300.5   (cps)Subst. — — — — — — — — Yes Yes Synergy^(@)

Example 4 Lack of Synergistic Effect on Viscosity (PolyvinylAlcohol+Chondroitin Sulfate+Polyvinylpyrrolidone)

[0033] The compositions shown in Table 4 were prepared and theirviscosity determined using a Brookfield cone/plate viscometer withnumber 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples(viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25°C.) for more viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 4. Airvol 523S is a commercially availablepolyvinyl alcohol polymer. Chondroitin sulfate is a commerciallyavailable polymer. K90 is a commercially available polyvinylpyrrolidonepolymer. TABLE 4 Composition (% w/v) Ingredient 19 20 21 22 23 24 25 26Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 PVA (Airvol 523S) — 0.2 — — 0.20.2 — 0.2 Chondroitin Sulfate — — 0.2 — 0.2 — 0.2 0.2 PVP (K90) — — —0.2 — 0.2 0.2 0.2 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pHpH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. 100    100    100    100    100   100    100    100    Viscosity(cps) 1.0 1.5 1.3 1.4 1.7 1.9 1.8  2.3*Subst. Synergy^(@) — — — — — — — No

Example 5 Lack of Synergistic Effect on Viscosity (PolyvinylAlcohol+Chondroitin Sulfate+Carbomer; PolyvinylAlcohol+Polyvinylpyrrolidone+Carbomer; ChondroitinSulfate+Polyvinylpyrrolidone+Carbomer)

[0034] The compositions shown in Table 5 were prepared and theirviscosity determined using a Brookfield cone/plate viscometer withnumber 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples(viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25°C.) for more viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 5. Airvol 523S is a commercially availablepolyvinyl alcohol polymer. Chondroitin sulfate is a commerciallyavailable polymer. K90 is a commercially available polyvinylpyrrolidonepolymer. The viscosities of the single polymer solutions for polyvinylalcohol, chondroitin sulfate and polyvinylpyrrolidone can be found inTable 4—Examples 20-22. TABLE 5 Composition (% w/v) Ingredient 27 28 2930 31 32 33 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 PVA — 0.2 — — — 0.2 0.2(Airvol 523S) Chondroitin Sulfate — — 0.2 — 0.2 0.2 — PVP — — — 0.2 0.2— 0.2 (K90) Carbopol 974P 0.1 0.1 0.1 0.1 0.1 0.1 0.1 NaOH/HCl q.s. q.s.q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.07.0 Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. 100    100   100    100    100    100    100    Viscosity (cps) 441.6  323.8  12.7 N/A*  16.7** 14.2  N/A* Subst. Synergy^(@) — — — — — No No

Example 6 Synergistic Effect on Viscosity (HPMC+HEC+Guar;HPMC+HEC+Carbomer)

[0035] The compositions shown in Table 6 were prepared and theirviscosity determined using a Brookfield cone/plate viscometer withnumber 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples(viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25°C.) for more viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 6. TABLE 6 Composition (% w/v) Ingredient 3435 36 37 38 39 40 41 42 43 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.04.0 HPMC — 0.3 — — — 0.3 — — 0.3 0.3 2910 HP-Guar — — 0.1 — — — 0.1 —0.1 — Carbopol — — — 0.1 — — — 0.1 — 0.1 974P Dextran — — — — 0.1 0.10.1 0.1 0.1 0.1 70 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.q.s. pH pH pH pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.07.0 Purified q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Water100    100    100    100    100    100    100    100    100    100   Viscosity 1.1 7.9 5.2 461.6  1.4 8.4 5.2 379.3  46.1  829.2  (cps)Subst. — — — — — — — — Yes Yes Synergy^(@)

Example 7 The Effect of Polymer Ratio on Viscosity

[0036] The effect of polymer ratio on viscosity was determined bypreparing compositions containing a ratio of the three designatedpolymers that varied from 1:1:1 to 3:3:3. The compositions are shown inTable 5. The viscosity was determined using a Bohlin Rheometer ModelCS-10 at 25° C. (shear rate: 0.8 1/s). Two people independently preparedthe indicated compositions and determined viscosity values (n=10 foreach person). The averages of the results are shown in Table 7. TABLE 7Composition (% w/v) Ingredient 44 45 46 47 48 Mannitol 4.0 4.0 4.0 4.04.0 HPMC 2910 0.1 0.1 0.1 0.3 0.3 Carbopol 0.1 0.1 0.3 0.1 0.3 974PHP-Guar 0.1 0.3 0.1 0.1 0.3 NaOH/HCl q.s. pH 7.0 q.s. pH 7.0 q.s. pH 7.0q.s. pH 7.0 q.s. pH 7.0 Purified q.s. 100 q.s. 100 q.s. 100 q.s. 100q.s. 100 Water Polymer ratio 1:1:1 1:1:3 1:3:1 3:1:1 3:3:3 HPMC:Carbopol: HP-Guar Viscosity 2865 8450 101950 3660 145000 (cps) [700][1655] [2899] [141] [1414] [Stnd. Deviation]

Example 8 Effect of Salt on Viscosity for a Polymer Combination thatContains Carbomer

[0037] The compositions shown below in Table 8 were prepared todetermine the effect of the addition of salt (NaCl) on viscosity. Theviscosity of each sample was determined using a Brookfield cone/plateviscometer (52 cone, 3 rpm). The results are shown in Table 8. TABLE 8Composition (% w/v) INGREDIENT Ex. 1 X Y Z AA Mannitol 4.0 4.0 4.0 4.04.0 HPMC 29.0 0.3 0.3 0.3 0.3 0.3 Carbopol 974P 0.1 0.1 0.1 0.1 0.1 HPGuar 0.1 0.1 0.1 0.1 0.1 NaCl 0 0.001 0.005 0.01 0.05 NaOH/HCl q.s. pH7.0 q.s. pH 7.0 q.s. pH 7.0 q.s. pH 7.0 q.s. pH 7.0 Purified Water q.s.100 q.s. 100 q.s. 100 q.s. 100 q.s. 100 Viscosity (cps) 1569 1382 774608 202

Example 9 Effect of Boric Acid on Viscosity for a Polymer Combinationthat Contains Carbomer

[0038] The compositions shown below in Table 9 were prepared todetermine the effect of the addition of boric acid on viscosity. Theviscosity of each sample was determined using a Brookfield cone/plateviscometer (52 cone, 3 rpm). The results are shown in Table 9. TABLE 9Composition (% w/v) INGRE- DIENT Ex. 1 X Y Z AA Mannitol 4.0 4.0 4.0 4.04.0 HPMC 2910 0.3 0.3 0.3 0.3 0.3 Carbopol 0.1 0.1 0.1 0.1 0.1 974P HPGuar 0.1 0.1 0.1 0.1 0.1 Boric acid 0 0.001 0.005 0.01 0.05 NaOH/HClq.s. pH 7 q.s. pH 7 q.s. pH 7 q.s. pH 7 q.s. pH 7 Purified q.s. 100 q.s.100 q.s. 100 q.s. 100 q.s. 100 Water Viscosity 1250 1035 682 531 172(cps)

Example 10 Effect of Total Polymer Concentration on Viscosity

[0039] The effect of total polymer concentration on the viscosity ofcompositions containing a combination of HPMC 2910, HP-Guar and Carbopol974P was evaluated using 5 compositions containing only the threedesignated polymers, mannitol and purified water. In each case, thecomposition contained 4.0% (w/w) of mannitol and had an adjusted pH of7.0. The total polymer concentrations ranged from 0.1 to 1.0, with theratio of polymers held constant at 3:1:1 (HPMC:HP-Guar:Carbopol). Theviscosity was determined using a Bohlin Rheometer Model CS-10 at 25° C.(shear rate: 0.8 1/s). The results (average of 10 measurements, n=10)are shown in Table 10 and FIG. 2. TABLE 10 Total Polymer Concentration(% w/v) Viscosity (cps) 0.1 48 0.25 83 0.5 3087 0.75 21,099 1.0 44,064

[0040] The invention has been described by reference to certainpreferred embodiments; however, it should be understood that it may beembodied in other specific forms or variations thereof without departingfrom its spirit or essential characteristics. The embodiments describedabove are therefore considered to be illustrative in all respects andnot restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description.

What is claimed is:
 1. An aqueous composition suitable for topicalophthalmic administration comprising three polymeric ingredients havinga synergistic effect on the composition's viscosity wherein the threepolymeric ingredients are hydroxypropyl methylcellulose and acombination of two polymers selected from the group of combinationsconsisting of guar gum and a carboxyvinyl polymer; guar gum andhydroxyethyl cellulose; guar gum and dextran; hydroxyethyl cellulose anda carboxyvinyl polymer; and dextran and a carboxyvinyl polymer, providedthat if the composition comprises a carboxyvinyl polymer then thecomposition does not contain sodium chloride or boric acid.
 2. Thecomposition of claim 1 wherein the guar gum ingredient is hydroxypropylguar.
 3. The composition of claim 1 wherein the carboxyvinyl polymer isa polymer of acrylic acid crosslinked with allyl sucrose orallylpentaerythritol.
 4. The composition of claim 1 wherein the threepolymeric ingredients are present in a ratio of 1:1:1 to 3:3:3, and thetotal concentration of the three polymeric ingredients ranges from0.1-1% (w/v).
 5. The composition of claim 4 wherein the totalconcentration of the three polymeric ingredients ranges from 0.3-0.9%(w/v).
 6. The composition of claim 5 wherein the total concentration ofthe three polymeric ingredients ranges from 0.4-0.7% (w/v).
 7. Thecomposition of claim 1 further comprising an ingredient selected fromthe group consisting of pharmaceutically acceptable buffering agents;preservatives; non-ionic tonicity-adjusting agents; surfactants;solubilizing agents; stabilizing agents; comfort-enhancing agents;emollients; pH-adjusting agents; and lubricants.
 8. The composition ofclaim 1 further comprising an ophthalmic drug.
 9. The composition ofclaim 9 wherein the ophthalmic drug is selected from the groupconsisting of anti-glaucoma agents; anti-angiogenesis agents;anti-infective agents; non-steroidal and steroidal anti-inflammatoryagents; growth factors; immunosuppressant agents; and anti-allergicagents.
 10. An aqueous composition for use as an artificial tear whereinthe composition consists essentially of hydroxypropyl methylcellulose; acarboxyvinyl polymer; hydroxypropyl guar; and mannitol, wherein thecomposition has a pH of 6.5-7.5 and an osmolality in the range of235-260 mOsm/kg.
 11. A method of alleviating the symptoms of dry eyecomprising topically administering to the eye a composition comprisingthree polymeric ingredients having a synergistic effect on thecomposition's viscosity wherein the three polymeric ingredients arehydroxypropyl methylcellulose and a combination of two polymers selectedfrom the group of combinations consisting of guar gum and a carboxyvinylpolymer; guar gum and hydroxyethyl cellulose; guar gum and dextran;hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and acarboxyvinyl polymer, provided that if the composition comprises acarboxyvinyl polymer then the composition does not contain sodiumchloride or boric acid.
 12. The method of claim 11 wherein the guar gumingredient is hydroxypropyl guar.
 13. The method of claim 11 wherein thecarboxyvinyl polymer is a polymer of acrylic acid crosslinked with allylsucrose or allylpentaerythritol.
 14. The method of claim 11 wherein thethree polymeric ingredients are present in a ratio of 1:1:1 to 3:3:3,and the total concentration of the three polymeric ingredients rangesfrom 0.1-1% (w/v).
 15. The method of claim 14 wherein the totalconcentration of the three polymeric ingredients ranges from 0.3-0.9%(w/v).
 16. The method of claim 11 wherein the composition consistsessentially of hydroxypropyl methylcellulose; a carboxyvinyl polymer;hydroxypropyl guar; and mannitol, wherein the composition has a pH of6.5-7.5 and an osmolality in the range of 235-260 mOsm/kg.